Chang 2011 Thesis

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Chang H-HG (2011) Mechanisms underlying the abnormal inositol metabolisms in diabetes mellitus. The University of Auckland, Department of Biological Sciences, PhD Thesis: 216 pp.

» https://researchspace.auckland.ac.nz/bitstream/handle/2292/7154/whole.pdf?sequence=3

Chang H-HG (2011) Thesis

Abstract: See Free Text

Keywords: inisotol metabolisms; diabetes

O2k-Network Lab: NZ Auckland Hickey AJ


Labels: Pathology: Diabetes 

Organism: Rat  Tissue;cell: Kidney  Preparation: Intact organ 



HRR: Oxygraph-2k 


Abnormal inositol metabolisms in diabetes comprise depletion of intracellular myoinositol (MI) content and increased urinary excretion of MI and D-chiro-inositol (DCI). Whilst intracellular MI depletion is implicated in the development of long term diabetic complications, the mechanisms underlying this depletion and its relationship with the increased urinary inositol excretion remain unknown. Therefore the overall aim of this thesis was to investigate the possible mechanisms for these inositol abnormalities in diabetic conditions using two approaches. First, the expression of key genes/proteins involved in maintaining intracellular MI levels (referred as inositol regulatory genes/proteins in this thesis) were investigated under diabetic conditions in nine major organs. These genes comprise sodium-dependent myo-inositol transporter subtype 1 and 2 (SMIT1, SMIT2), proton-dependent myo-inositol transporter (HMIT), myo-inositol phosphate synthase (MIPS), inositol monophosphatase (IMP) and myo-inositol oxygenase (MIOX). Second, an isolated perfused kidney system was employed to investigate the phenomenon of increased urinary inositol excretion in diabetes. The data generated in this thesis showed that depletion of MI occurred in the kidneys from hyperglycaemic, hypertensive and insulin resistant/obese animal models (Chapter 3). In all cases, the observed MI depletion was accompanied with an enhanced MIOX expression, at both mRNA and protein levels and with an elevated MIOX activity. In particular, MI depletion was also observed in animal models of hypertension and insulin resistance/obesity, where high glucose ambience was absent. These findings suggest that MI depletion in the kidney is not directly attributable to hyperglycaemia per se and may instead reflect in one aspect the up-regulation of the glucuronate-xylulose pathway as indicated by the elevated MIOX expression and activity. Besides kidney, MI depletion has also been reported in other tissues such as nerve and lens. Therefore the expression of inositol regulatory genes was investigated in the extrarenal tissues under diabetic conditions (Chapter 4). MI deficiency was indeed observed in liver, sciatic nerve and lens in streptozotocin (STZ)-induced diabetic rats. In particular, the data generated from the liver study provide the first evidence that MI depletion occurs in an insulin-sensitive tissue. This tissue-specific depletion in MI was retained following exposure to diabetes for 8 weeks. In contrast, MI level remained unchanged in soleus muscle, heart, lung, spleen, and brain of both 4- and 8-week diabetic rats. Whilst the gene expression of inositol regulatory genes was unaltered in tissues without MI depletion, the liver, nerve, and lens nevertheless displayed some interesting expression profiles. The up-regulation of MIOX in diabetic kidneys and livers, the down-regulation of both SMIT1 and HMIT in diabetic nerves and the elevation in the expression of aldose reductase could be responsible for the observed intra-tissue MI depletion. In the second study, an isolated perfused kidney system was used to investigate the relationship between excess urinary inositol excretion and high glucose ambience in the diabetic kidney (Chapter 5). Compared to the non-diabetic kidney, the STZ-induced diabetic kidney displayed impaired MI and DCI reabsorption, regardless of the glucose concentration. In addition, a weak correlation between high glucose and reduced DCI reabsorption was observed whereas MI reabsorption was not influenced by high glucose. These findings showed that the primary cause of excess urinary secretion of both MI and DCI is probably due to fundamental changes in the kidney as a result of prolonged exposure to diabetes rather than the transient inhibitory effect of high glucose per se.